AIMS: As many as 50% of AIDS patients suffer from multiple neurological symptoms collectively termed AIDS-related dementia. The neurotoxicity of the HIV-1 and its envelope protein gp120 has been implicated in the neuropathology of AIDS. Results from several lines of research suggest that HIV or gp120 cause the death of neurons through the activation of microglia which release neurotoxic substances, such as proinflammatory cytokines and nitric oxide (NO). However, the mechanisms underlying the regulation of HIV replication in microglia is still lscking. The purpose of this project is to elucidate the signal pathways rerulating the promoter activity of HIV in microglia cultures.ACCOMPLISHMENTS: Cerebral inflammation often occurs in immunodeficiency virus (HIV) infected patients with dementia. Inflammation orchestrated by microglia will in turn stimulate HIV replication. Increasing lines of evidence have shown that p38 kinase pathway play important roles in the regulation of the expression of immune modulators in microglia stimulated by inflammatory factors. Therefore, this study aims to elucidate the significance of p38 kinase in bacterial endotoxin lipopolysaccharide (LPS)-stimulated HIV long-term repeated (LTR) promoter in microglia. A murine microglial cell line BV2 transfected with pLTR-luc and luciferase serves as a reporter gene. While LPS (1 ng/ml) stimulated 2.3-fold increase in luciferase activity, other cytokines such as interleukin-1, interlukin-6 and tumor necrosis factor-a did not show significant change of the luciferase activity. Inhibitor for p38 kinase SB202190 markedly reduced LPS-stimulated HIV-LTR with a maximum inhibition about 80% when microglia were treated with 0.5 ?M of SB202190. By using serial mutation of HIV-LTR to study the importance of different promoter regions, NF-kB sites was shown to be essential for LPS to stimulate HIV-LTR. However, Sp1 and upstream AP1 sites show little effect, suggesting the significance of NFkB in LTR-directed gene expression. Further study the possible linkages of p38 kinase and NF-kB signaling by western blot analysis, the result demonstrated that SB202190 inhibited LPS-induced phosphorylation of an NFkB inhibitor, IkBa. Taken together, the study provides evidence that p38 kinase pathway, an important cellular signaling for inflammation, plays significant roles in the activation of HIV-LTR by immune stimulant such as LPS. Studies in this direction should provide a new avenue for future therapeutic intervention of HIV-infected patients.